Colorectal Tumors Research Articles

Development of a First-in-Class DNMT1/HDAC Inhibitor with Improved Therapeutic Potential and Potentiated Antitumor Immunity.

Epigenetic therapies have emerged as a key paradigm for treating malignancies. In this study, a series of DNMT1/HDAC dual inhibitors were obtained by fusing the key pharmacophores from DNMT1 inhibitors (DNMT1i) and HDAC inhibitors (HDACi). Among them, compound (R)-23a demonstrated significant DNMT1 and HDAC inhibition both in vitro and in cells and largely phenocopied the synergistic effects of combined DNMT1i and HDACi in reactivating epigenetically silenced tumor suppressor genes (TSGs). This translated into a profound tumor growth inhibition (TGI = 98%) of (R)-23a in an MV-4-11 xenograft model, while displaying improved tolerability compared with single agent combination. Moreover, in a syngeneic MC38 mouse colorectal tumor model, (R)-23a outperformed the combinatory treatment in reshaping the tumor immune microenvironment and inducing tumor regression. Collectively, the novel DNMT1/HDAC dual inhibitor (R)-23a effectively reverses the cancer-specific epigenetic abnormalities and holds great potential for further development into cancer therapeutic agents.

Retrospective study evaluating association of colorectal tumors and hepatitis C virus.

Chronic hepatitis C virus (HCV) has been associated with hepatic and extrahepatic malignancies. Limited studies have shown an association between colorectal adenomas and HCV populations. To study the prevalence of colorectal adenomas in patients with HCV compared to the general population and to evaluate if it is an independent risk factor for colorectal adenomas. Patients were divided into HCV and non-HCV based on their HCV RNA titers. Patients with alcoholic liver disease, hepatitis B infection, and inflammatory bowel disease were excluded. Continuous variables were analyzed using the Mann-Whitney U test, and categorical variables using χ 2 with P < 0.05 were considered statistically significant. The significant covariates (independent variables) were matched in both groups by propensity score matching, followed by multivariate regression analysis. Of the 415 patients screened, 109 HCV patients and 97 non-HCV patients with colonoscopy results were included in the study. HCV patients were older, had a smoking history, had less frequent aspirin use, and had a lower body mass index (BMI) (P < 0.05). The HCV cohort had a significantly increased number of patients with adenomas (adenoma detection rate of 53.2% vs 34%. P = 0.006). We performed a propensity-matched multivariate analysis where HCV infection was significantly associated with colorectal adenoma (OR: 2.070, P = 0.019). Our study shows a significantly higher rate of adenomas in HCV patients compared to the general population. Prospective studies would help determine if the increase in adenoma detection lowers the risk for colorectal cancer.

Targeting CBP and p300: Emerging Anticancer Agents.

CBP and p300 are versatile transcriptional co-activators that play essential roles in regulating a wide range of signaling pathways, including Wnt/β-catenin, p53, and HIF-1α. These co-activators influence various cellular processes such as proliferation, differentiation, apoptosis, and response to hypoxia, making them pivotal in normal physiology and disease progression. The Wnt/β-catenin signaling pathway, in particular, is crucial for cellular proliferation, differentiation, tissue homeostasis, and embryogenesis. Aberrant activation of this pathway is often associated with several types of cancer, such as colorectal tumor, prostate cancer, pancreatic and hepatocellular carcinomas. In recent years, significant efforts have been directed toward identifying and developing small molecules as novel anticancer agents capable of specifically inhibiting the interaction between β-catenin and the transcriptional co-activators CBP and p300, which are required for Wnt target gene expression and are consequently involved in the regulation of tumor cell proliferation, migration, and invasion. This review summarizes the most significant and original research articles published from 2010 to date, found by means of a PubMed search, highlighting recent advancements in developing both specific and non-specific inhibitors of CBP/β-catenin and p300/β-catenin interactions. For a more comprehensive view, we have also explored the therapeutic potential of CBP/p300 bromodomain and histone acetyltransferase inhibitors in disrupting the transcriptional activation of genes involved in various signaling pathways related to cancer progression. By focusing on these therapeutic strategies, this review aims to offer a detailed overview of recent approaches in cancer treatment that selectively target CBP and p300, with particular emphasis on their roles in Wnt/β-catenin-driven oncogenesis.

PIPAC Pharmacologic and Clinical Data.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) emerged as an innovative intraperitoneal chemotherapy delivery system to overcome the issue of limited efficacy of systemic therapies to induce response in peritoneal malignancies. Promising results for patients with mesothelioma peritonei and peritoneal metastasis from gastric, ovarian, colorectal, pancreatic, and hepatobiliary tumors origin are changing the landscape for patients otherwise just facing palliative treatment. Ongoing trials will shed more light on the actual benefits of PIPAC.

Oncolytic adenovirus encoding decorin and CD40 ligand inhibits tumor growth and liver metastasis via immune activation in murine colorectal tumor model

Colorectal cancer (CRC) is the second common cause of cancer mortality worldwide, and it still lacks effective approaches for relapsed and metastatic CRC. Recently, oncolytic virus has been emerged as a promising immune therapeutic strategy. In this study, we develop a novel oncolytic adenovirus, rAd.mDCN.mCD40L, which drive oncolytic activity by telomerase reverse transcriptase promoter (TERTp). rAd.mDCN.mCD40L expressed both mouse genes of decorin (mDCN) and CD40 ligand (mCD40L), and produced effective cytotoxicity in both human and mouse CRC cells. Moreover, oncolytic adenovirus mediated mDCN over-expression inhibited Met expression in vitro. In CT26 subcutaneous tumor model, intratumorally delivery of oncolytic adenoviruses could inhibit tumor growth and liver metastasis, while mDCN and/or mCD40L armed oncolytic adenoviruses produced much more impressive responses. No obvious toxicity was detected in lung, liver and spleen. Moreover, mDCN and/or mCD40L armed oncolytic adenoviruses altered the immune state to activate anti-tumor responses, including increasing CD8+ T effector cells and CD4+ memory T cells, reducing MDSCs and Tregs in peripheral blood. Furthermore, mDCN and/or mCD40L armed oncolytic adenoviruses mediated mDCN and/or mCD40L expression in tumors, and up-regulated Th1 cytokines and reduced Th2 cytokines in tumors, which will be benefit for remodeling tumor microenvironment. Importantly, rAd.mDCN.mCD40L and rAd.mCD40L prevented tumor liver metastasis much more effectively than rAd.Null and rAd.mDCN. Therefore, rAd.mDCN.mCD40L and rAd.mCD40L are promising approaches for CRC therapy.

The Significance of C-Reactive Protein Value and Tumor Grading for Malignant Tumors: A Systematic Review.

Malignant tumors represent a significant pathology with a profound global impact on the medical system. The fight against cancer represents a significant challenge, with multidisciplinary teams identifying numerous areas requiring improvement to enhance the prognosis. Facilitating the patient's journey from diagnosis to treatment represents one such area of concern. One area of research interest is the use of various biomarkers to accurately predict the outcome of these patients. A substantial body of research has been conducted over the years examining the relationship between C-reactive protein (CRP) and malignant tumors. The existing literature suggests that combining imaging diagnostic modalities with biomarkers, such as CRP, may enhance diagnostic accuracy. A systematic review was conducted on the PubMed and Web of Science platforms with the objective of documenting the interrelationship between CRP value and tumor grading for malignant tumors. After the application of the exclusion and inclusion criteria, 17 studies were identified, published between 2002 and 2024, comprising a total of 9727 patients. These studies indicate this interrelationship for soft tissue sarcomas and for renal, colorectal, esophageal, pancreatic, brain, bronchopulmonary, ovarian, and mesenchymal tumors. Elevated CRP levels are correlated with higher grading, thereby underscoring the potential utility of this biomarker in clinical prognostication.

Food antigens suppress small intestinal tumorigenesis.

Food components suppressing small intestinal tumorigenesis are not well-defined partly because of the rarity of this tumor type compared to colorectal tumors. Using Apcmin/+ mice, a mouse model for intestinal tumorigenesis, and antigen-free diet, we report here that food antigens serve this function in the small intestine. By depleting Peyer's patches (PPs), immune inductive sites in the small intestine, we found that PPs have a role in the suppression of small intestinal tumors and are important for the induction of small intestinal T cells by food antigens. On the follicle-associated epithelium (FAE) of PPs, microfold (M) cells pass food antigens from lumen to the dendritic cells to induce T cells. Single-cell RNA-seq (scRNA-seq) analysis of immune cells in PPs revealed a significant impact of food antigens on the induction of the PP T cells and the antigen presentation capacity of dendritic cells. These data demonstrate the role of food antigens in the suppression of small intestinal tumorigenesis by PP-mediated immune cell induction.

The role of Fusobacterium nucleatum in the pathogenesis of colon cancer.

Previously, many studies have reported changes in the gut microbiota of patients with colorectal cancer (CRC). While CRC is a well-described disease, the relationship between its development and features of the intestinal microbiome is still being understood. Evidence linking Fusobacterium nucleatum enrichment in colorectal tumor tissue has prompted the elucidation of various molecular mechanisms and tumor-promoting attributes. In this review we highlight various aspects of our understanding of the relationship between the development of CRC and the alteration of intestinal microbiome, focusing specifically on the role of F. nucleatum. As the amount of F. nucleatum DNA in CRC tissue is associated with shorter survival, it may potentially serve as a prognostic biomarker, and most importantly may open the door for a role in CRC treatment.

The up-regulation of SYNCRIP promotes the proliferation and tumorigenesis via DNMT3A/p16 in colorectal cancer

Heterogeneous nuclear ribonucleoproteins (hnRNPs), a group of proteins that control gene expression, have been implicated in many post-transcriptional processes. SYNCRIP (also known as hnRNP Q), a subtype of hnRNPs, has been reported to be involved in mRNA splicing and translation. In addition, the deregulation of SYNCRIP was found in colorectal cancer (CRC). However, the role of SYNCRIP in regulating CRC growth remains largely unknown. Here, we found that SYNCRIP was highly expressed in colorectal cancer by analyzing TCGA and GEPIA database. Furthermore, we confirmed the expression of SYNCRIP expression in CRC tumor and CRC cell lines. Functionally, SYNCRIP depletion using shRNA in CRC cell lines (SW480 and HCT 116) resulted in increased caspase3/7 activity and decreased cell proliferation, as well as migration. Meanwhile, overexpression of SYNCRIP showed opposite results. Mechanistically, SYNCRIP regulated the expression of DNA methyltransferases (DNMT) 3A, but not DNMT1 or DNMT3B, which affected the expression of tumor suppressor, p16. More importantly, our in vivo experiments showed that SYNCRIP depletion significantly inhibited colorectal tumor growth. Taken all together, our results suggest SYNCRIP as a potent therapeutic target in colorectal cancer.

Clinical significance of peripheral blood UL16 and DR-70 for the early diagnosis and prognostic evaluation of colorectal cancer.

Early diagnosis of colorectal cancer (CRC) is of great significance to improve the survival rate and quality of life of patients, but early diagnosis of CRC requires more sensitive techniques. Peripheral blood UL16-binding protein 2 (ULBP2) and human fibrinogen degradation products (DR-70) are the main indicators for the diagnosis of malignant tumors. To assess ULBP2 and DR-70 potential for the early diagnosis and prognostic evaluation of CRC to provide a reference. This study involved 60 patients with early-stage CRC (CRC group), 50 patients with benign colorectal tumors (benign group), and 50 healthy patients (control group) enrolled at the Affiliated Hospital of Jiangnan University and Jiangsu Province Official Hospital between January, 2020 and January, 2022. ULBP2 and DR-70 levels in the blood were determined and differences among the three groups and early diagnostic values for CRC were determined. Patients with CRC were divided into the good prognosis and poor prognosis groups, and ULBP2 and DR-70 levels in the blood and diagnostic values were compared. ULBP2 and DR-70 serum levels were significantly higher in the CRC group than in the control and benign groups (P < 0.05); however, no significant differences were observed between the benign and control groups (P > 0.05). Among the 60 patients with CRC followed up for two years, two died (3.33%) and 15 exhibited tumor metastasis, progression, or recurrence (25.00%). ULBP2 and DR-70 serum levels were significantly higher in the poor prognosis group than in the good prognosis group (P < 0.05). A receiver operating characteristic curve was plotted. Area under the curve, sensitivity, and specificity of serum ULBP2 with DR-70 for the early diagnosis of CRC were higher than those of the single serum indices (P < 0.05) in both the good and poor prognosis groups. ULBP2 and DR-70 serum levels were significantly high in patients with early-stage CRC. They improved the diagnostic rate of early-stage CRC and predicted patient prognosis, thereby showing clinical application potential.

Achieving sub-millisievert CT colonography for accurate colorectal tumor detection using smart examination protocols: a prospective self-controlled study.

To assess the feasibility of combining Auto-kVp selection technique, higher preset ASIR-V and noise index (NI) to realize individualized sub-mSv CT colonography (CTC) for accurate colorectal tumor detection and localization. Ninety patients with suspected colorectal cancer (CRC) were prospectively enrolled to undergo standard dose CTC (SDCTC) in the prone and ultra-low dose CTC (ULDCTC) in the supine position. SDCTC used 120 kVp, preset ASIR-V of 30%, SmartmA for a NI of 13; ULDCTC used Auto-kVp selection technique with 80 or 100 kVp, preset ASIR-V of 60%, SmartmA for a NI of 13 for 80 kVp, and NI of 15 for 100 kVp. The effective dose (ED), image quality [signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of colorectal neoplasms] between the two protocols were compared and the accuracies of tumor locations were evaluated for CTC in comparison with the surgery results. The mean ED of the ULDCTC-80 kVp subgroup was 0.70 mSv, 71.43% lower than the 2.45mSv for the 120 kVp group, while that of the ULDCTC-100 kVp subgroup was 0.98mSv, 73.00% lower than the 3.63mSv for the 120 kVp group (P < 0.001). The tumor SNR and CNR of the ULDCTC were higher than those of SDCTC (P < 0.05), while there was no difference in the subjective image quality between them with good inter-observer agreement (Kappa: 0.805-0.923). Both SDCTC and ULDCTC groups had high detection rate of colorectal tumors, along with good consistency in determining tumor location compared with surgery reports (Kappa: 0.718-0.989). The combination of Auto-kVp selection, higher preset ASIR-V and NI achieves individualized sub-mSv CTC with good performance in detecting and locating CRC with surgery and consistent results between SDCTC and ULDCTC.

Design, Synthesis, and Biological Evaluation of 5-Amino-4-fluoro-1H-benzo[d]imidazole-6-carboxamide Derivatives as Novel and Potential MEK/RAF Complex Inhibitors Based on the "Clamp" Strategy.

Herein, we described the rational drug design and synthesis of a series of 5-amino-4-fluoro-1H-benzo[d]imidazole-6-carboxamide derivatives that inhibit MEK and RAF kinases. The detailed screening cascades revealed that 16b was a preferred compound, which might act like a "clamp" to stabilize the MEK/RAF complex, thereby effectively inhibiting MEK1, BRAF, and BRAFV600E with IC50 values of 28, 3, and 3 nM, respectively. 16b possessed an excellent selectivity over other 312 human-related kinases at 1 μM. In vitro, 16b showed potent antiproliferative activities against MIA PaCa-2 (G12C KRAS), HCT116 (G13D KRAS), and C26 (G12D KRAS) cells with IC50 values of 0.011, 0.079, and 0.096 μM, respectively. CoIP experiments demonstrated that 16b could induce MEK/RAF complex formation. Most importantly, in the C26 syngeneic colorectal and HCT116 mice xenograft tumor models, 16b demonstrated tumor growth inhibition of 70 and 93%, respectively, suggesting that 16b may be a promising MEK/RAF complex inhibitor and worthy of further development.

ImmunoPET imaging of EpCAM in solid tumours with nanobody tracers: a preclinical study.

Epithelial cell adhesion molecule (EpCAM) is a potential therapeutic target and anchoring molecule for circulating and disseminated tumour cells (CTC/DTC) in liquid biopsy. In this study, we aimed to construct EpCAM-specific immuno-positron emission tomography (immunoPET) imaging probes and assess the diagnostic abilities in preclinical cancer models. By engineering six single-domain antibodies (e.g., EPCD1 - 6) targeting EpCAM of different binding properties and labelling with 68Ga (T1/2 = 1.1 h) and 18F (T1/2 = 110 min), we developed a series of EpCAM-targeted immunoPET imaging probes. The probes' pharmacokinetics and diagnostic accuracies were investigated in cell-derived human colorectal (LS174T) and esophageal cancer (OE19) tumour models. Based on in vitro binding affinities and in vivo pharmacokinetics of the first three tracers ([68Ga]Ga-NOTA-EPCD1, [68Ga]Ga-NOTA-EPCD2, and [68Ga]Ga-NOTA-EPCD3), we selected [68Ga]Ga-NOTA-EPCD3 for tumour imaging which showed an average tumour uptake of 2.06 ± 0.124%ID/g (n = 3) in LS174T cell-derived tumour model. Development and characterisation of [18F]AIF-RESCA-EPCD3 showed comparable tumour uptake of 1.73 ± 0.0471%ID/g (n = 3) in the same tumour model. Further validation of [68Ga]Ga-NOTA-EPCD3 in OE19 cell-derived tumour model showed an average tumour uptake of 4.27 ± 1.16%ID/g and liver uptake of 13.5 ± 1.30%ID/g (n = 3). Near-infrared fluorescence imaging with Cy7-EPCD3 confirmed the in vivo pharmacokinetics and relatively high liver accumulation. We further synthesized another three 18F-labeled nanobody tracers ([18F]AIF-RESCA-EPCD4, [18F]AIF-RESCA-EPCD5, and [18F]AIF-RESCA-EPCD6) and found that [18F]AIF-RESCA-EPCD6 had the best pharmacokinetics with low background. [18F]AIF-RESCA-EPCD6 showed explicit uptake in the subcutaneously inoculated OE19 tumour model with an average uptake of 4.70 ± 0.26%ID/g (n = 3). In comparison, the corresponding tumour uptake (0.17 ± 0.25%ID/g, n = 3) in the EPCD6 blocking group was substantially lower (P < 0.001), indicating the targeting specificity of the tracer. We developed a series of 68Ga/18F-labeled nanobody tracers targeting human EpCAM. ImmunoPET imaging with [18F]AIF-RESCA-EPCD6 may facilitate better use of EpCAM-targeted therapeutics by noninvasively displaying the target's expression dynamics.

Morbidity and Postoperative Mortality of Colorectal Tumors

Colorectal cancer, by its frequency and severity, represents a serious public health problem worldwide. In Morocco, the incidence of colorectal cancer is constantly increasing. Post-operative morbidity and mortality is an event whose evaluation and analysis are necessary to improve surgical results and optimize patient care. Thus, knowledge of the causes and risk factors of morbidity and mortality will contribute not only to a better evaluation of patients candidates for colorectal surgery, but also to reveal new avenues of research to improve the post-operative prognosis of these patients. The objective of this retrospective work is to carry out an epidemiological study of the morbidity and mortality of patients admitted during the postoperative period of colorectal surgery to the surgical intensive care unit of the Ibn Rochd University Hospital in Casablanca; as well as the search for potential predictive factors associated with it.

Universal screening of colorectal tumors for lynch syndrome: a survey of patient experiences and opinions

BackgroundLynch syndrome represents the most common hereditary cause of both colorectal and endometrial cancer. It is caused by defects in mismatch repair genes, as well as EPCAM. Universal screening of colon tumors for Lynch syndrome via microsatellite instability (MSI) and/or immunohistochemistry (IHC) can identify patients and families at risk to develop further cancers and potentially impact surveillance and treatment options. The approach to implementation of universal screening, taking ethical considerations into account, is critical to its effectiveness, with patient perspectives providing valuable insight.MethodsPatients whose colon tumors underwent universal screening at Penn State Hershey Medical Center over a period of 2.5 years were mailed a survey on universal screening in 2017. Along with the survey, they received a recruitment letter and a summary explanation of research. The survey included both multiple choice and free-response questions that covered topics including respondent knowledge of Lynch syndrome, attitudes toward universal screening and experiences with the screening protocol as implemented.ResultsSixty-six of 297 possible patients (22.2%) responded to the survey, including 13 whose screening results raised concern for Lynch syndrome. 75.8% of respondents supported universal tumor screening without informed consent. 92.4% preferred receiving screening results regardless of outcome. Respondents described benefits to screening for themselves and their families.ConclusionsWhile broadly supporting universal tumor screening without informed consent, respondents also wanted more information shared about the screening policy, as well as their results. These patient preferences should be one of many factors considered when implementing universal screening and can also inform practices regarding both tumor profiling and universal genetic testing, which is becoming more prevalent.

Heteroaryl derivatives of suvorexant as OX1R selective PET ligand candidates: Cu-mediated 18F-fluorination of boroxines, in vitro and initial in vivo evaluation

BackgroundThe orexin receptor (OXR) plays a role in drug addiction and is aberrantly expressed in colorectal tumors. Subtype-selective OXR PET ligands suitable for in vivo use have not yet been reported. This work reports the development of 18F-labeled OXR PET ligand candidates derived from the OXR antagonist suvorexant and the OX1R-selective antagonist JH112.ResultsComputational analysis predicted that fluorine substitution (1e) and introduction of the fluorobenzothiazole scaffold (1f) would be suitable for maintaining high OX1R affinity. After multi-step synthesis of 1a–1f, in vitro OXR binding studies confirmed the molecular dynamics calculations and revealed single-digit nanomolar OX1R affinities for 1a–f, ranging from 0.69 to 2.5 nM. The benzothiazole 1f showed high OX1R affinity (Ki = 0.69 nM), along with 77-fold subtype selectivity over OX2R. Cu-mediated 18F-fluorination of boroxine precursors allowed for a shortened reaction time of 5 min to provide the non-selective OXR ligand [18F]1c and its selective OX1R congener [18F]1f in activity yields of 14% and 22%, respectively, within a total synthesis time of 52–76 min. [18F]1c and [18F]1f were stable in plasma and serum in vitro, with logD7.4 of 2.28 ([18F]1c) and 2.37 ([18F]1f), and high plasma protein binding of 66% and 77%, respectively. Dynamic PET imaging in rats showed similar brain uptake of [18F]1c (0.17%ID/g) and [18F]1f (0.15%ID/g). However, preinjection of suvorexant did not significantly block [18F]1c or [18F]1f uptake in the rat brain. Pretreatment with cyclosporine A to study the role of P-glycoprotein (P-gp) in limiting brain accumulation moderately increased brain uptake of [18F]1c and [18F]1f. Accordingly, in vitro experiments demonstrated that the P-gp inhibitor zosuquidar only moderately inhibited polarized, basal to apical transport of 1c (p < 0.05) and had no effect on the transport of 1f, indicating that P-gp does not play a relevant role in brain accumulation of [18F]1c and [18F]1f in vivo.ConclusionsThe in vitro and in vivo results of [18F]1c and [18F]1f provide a solid basis for further development of suitable OXR PET ligands for brain imaging.

Artificial Intelligence and cancer: Profile of registered clinical trials

Artificial Intelligence (AI) has made significant strides due to advancements in processing algorithms and data availability. Recent years have shown a resurgence in AI, driven by breakthroughs in deep machine learning. AI has attracted particular interest in the medical sector, especially in the field of personalized medicine, which for example uses large-scale genomic and molecular data to predict individual patient treatment responses. The applications of AI in disease diagnosis, monitoring, and treatment are expanding rapidly, leading to a growing number of registered trials. Therefore, this study aimed to identify and evaluate clinical trials registered between January 1st 2016, and September 30th 2023 that connect AI and cancer. Our findings show that the number of clinical trials linking AI with cancer research has grown significantly compared to other diseases, with colorectal and breast tumour types showing the highest number of registered trials. The most frequent intervention was disease diagnosis and monitoring. Regarding countries, China and the United States hold the highest numbers of registered trials. In conclusion, oncology is a field with a great interest in AI, where the developed countries are leading the studies in this field. Unfortunately, developing countries are still crawling in this aspect and government policies should be made to improve that area.

Risk of metachronous neoplasia in early-onset colorectal cancer: meta-analysis.

Metachronous colorectal cancer refers to patients developing a second colorectal neoplasia diagnosed at least 6 months after the initial cancer diagnosis, excluding recurrence. The aim of this systematic review is to assess the incidence of metachronous colorectal cancer in early-onset colorectal cancer (defined as age at diagnosis of less than 50 years) and to identify risk factors. This is a systematic review and meta-analysis performed following the PRISMA statement and registered on PROSPERO. The literature search was conducted in PubMed and Embase. Only studies involving patients with early-onset colorectal cancer (less than 50 years old) providing data on metachronous colorectal cancer were included in the analysis. The primary endpoint was the risk of metachronous colorectal cancer in patients with early-onset colorectal cancer. Secondary endpoints were association with Lynch syndrome, family history and microsatellite instability. Sixteen studies met the inclusion criteria. The incidence of metachronous colorectal cancer was 2.6% (95% c.i. 2.287-3.007). The risk of developing metachronous colorectal cancer in early-onset colorectal cancer versus non-early-onset colorectal cancer patients demonstrated an OR of 0.93 (95% c.i. 0.760-1.141). The incidence of metachronous colorectal cancer in patients with Lynch syndrome was 18.43% (95% c.i. 15.396-21.780), and in patients with family history 10.52% (95% c.i. 5.555-17.659). The proportion of metachronous colorectal cancer tumours in the microsatellite instability population was 19.7% (95% c.i. 13.583-27.2422). The risk of metachronous colorectal cancer in patients with early-onset colorectal cancer is comparable to those with advanced age, but it is higher in patients with Lynch syndrome, family history and microsatellite instability. This meta-analysis demonstrates the need to personalize the management of patients with early-onset colorectal cancer according to their risk factors.

Autofluorescent Cancer Stem Cells: Potential Biomarker to Predict Recurrence in Resected Colorectal Tumor.

Cancer stem cells (CSCs) in colorectal cancer (CRC) drive intratumoral heterogeneity and distant metastases. Previous research from our group showed that CSCs can be easily detected by autofluorescence (AF). The aim of the present study was to evaluate the potential role of AF CSCs as a prognostic biomarker for CRC relapse. Seventy-five freshly-resected tumors were analyzed, by flow cytometry. AF was categorized as high (H-AF) or low (L-AF), and results were correlated with histological features (grade of differentiation, presence of metastases in lymph nodes (LN), perivascular and lymphovascular invasion) and clinical variables (time to relapse and overall survival). Nineteen out of 75 (25.3%) patients experienced relapse (local or distant), 13 out of these 19 patients showed positive LNs and 6 patients had H-AF. Of note, 4 of them died before 5 years. While patients with H-AF CSCs percentages in the global population experienced 1.5 times increased relapse -HR 1.47, CI 95% (0.60 - 3.63), patients with H-AF CSC percentages and LN metastases had the highest risk of relapse; HR 7.92, p< 0.004, CI 95% (1.97 - 31.82). These data support AF as an accurate and feasible marker to identify CSCs in resected CRC. A strong statistical association between H-AF CSCs and the risk of relapse was observed, particularly in patients with positive LNs, suggesting that H-AF patients might benefit from adjuvant chemotherapy regimens and intensive surveillance due to their high propensity to experience disease recurrence.

Investigation of the Relationship Between DNA Mismatch Repair Genes and Microsatellite Instability in Solid Tumors

Aim: In this study, we aimed to detect the MSI status and somatic mutations in MMR genes (MSH2, MSH6, MLH1, PMS2) of a total of 55 solid tumors diagnosed with colorectal, endometrium and ovarian cancer by NGS method and to reveal the relationship between them. Material and Method: DNA isolation was performed by taking 10-micron sections from paraffin-embedded tissue samples of 55 patients diagnosed with kolorektal, endometrium ve ovarian solid tümörlerinin and Kapa NGS DNA extraction kit was used for sequence analysis. The purity and concentration of the DNA obtained was measured by Qubit fluoremeter, and NadPrep DNA Universal Library Preparation Kit was used for high quality library preparation. Bioinformatics analyses were performed on the Genomize Seq platform. The MSI value was analysed by Roche Navify Mutation Caller software and percentage MSI values were determined using the MSIsensor2 pipeline for secondary analysis of NGS. Results: All ovarian tumors were in the MSI-Stable category. The average MSI value was 2.01. One sample had an MSI of zero. In addition, no mutations in the MSH2 and MLH1 genes were detected in any of the ovarian tumors. 3 of 4 endometrial tumors were in the MSI-Stable category, and 1 tumor was in the MSI-low (MSI value: 13.2) category. No variants were detected in the MSH2 and PMS2 genes in endometrial tumors. 2 of the 41 colorectal tumors (Case4, Case16) were in the MSI-High category. No variants were detected in the MMR genes in 19 tumors. Conclusion: Although frame-shift and stop-gain mutations were detected in 23 tumors that would cause protein deficiency in MMR genes, MSI-H was not detected, as expected, except for two colorectal tumors. Therefore, the results of our study emphasise the need to define new predictive biomarkers clinically within the framework of algorithms to predict response to immunotherapy and determine prognosis.